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FAT-SOLUBLE VITAMINS 957

NutritionBiochemistry

P A R T

V

“What drives life... is a little electric current, kept up by sunshine.”

— Albert Szent-Györgyi : Chemistry of Muscular Contraction, 1960.

Fruits and vegetables are nutritious. Besides containing carbohydratesproteins, lipids, minerals and some fibres, they also possess appreciableamounts of vitamins which are sine quo non for life.

Contents

Contents

CONTENTS

• Historical Resume

• Definition

• General characteristics

• Classification

• Storage of Vitamins in theBody

• Daily Human Requirementsof Vitamins

• Avitaminoses (Deficienciesof Vitamins)

• Vitamin A

• Vitamin D

• Vitamin E

• Vitamin K

• Coenzyme Q

• Stigmasterol

Fat-SolubleVitamins

33C H A P T E R

HISTORICAL RESUME

Vitamins have a back-dated history. The dreadeddisease scurvy was one of the prevalent diseasesin Europe during 15th and 16th centuries. The

disease is said to have afflicted the crusadors. Scurvy wasreported by Vasco de Gama during his sea voyages andJacques Cartier in 1535 had reported death of about 25%of his sailing crew due to scurvy. On the recommendationof Sir James Lancaster, an English privateer, the ships ofEast India Company in 1601 carried oranges and lemonsto prevent scurvy. In 1757, James Lind, a British navalsurgeon, stated that fresh fruits and vegetables alone areeffective to protect the body from various maladies andurged the inclusion of lemon juice in the diet of sailorsto prevent scurvy. And some 40 years later, the Admiraltytook his advice. After limes were substituted for lemonsin 1865, British sailors began to be known as “limeys.”Similarly, rickets was also attributed to faulty diets andGuérin (1838) produced it experimentally in puppies toprove the dietary connection.

In 1887, Admiral Takaki, Director-General of theMedical Services in Japan, demonstrated that anotherscourge beriberi could be prevented by enriching the dietwith meat, vegetables and milk and at the same timedecreasing the amount of milled rice in the case of Japanese

Pictured above is a 2 1/2-year-old boy withsevere rickets, which is due to thedeficiency of vitamin D in the body. Thedisease was once common in cold climateswhere heavy clothing blocks the ultraviolet(UV) component of sunlight necessary forthe production of vitamin D3 in skin.Cholecalciferol, (vitamin D3) is produced inthe skin by UV irradiation of7-dehydrocholesterol, the provitamin form.In the liver, a hydroxyl group is added atC-25; in the kidney, a second hydroxylationat C-1 produces the active hormone, 1,25-dihydroxycholecalciferol. This hormoneregulates the metabolism of Ca2+ in kidney,intestine, and bone. Dietary vitamin Dprevents rickets.

959

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960 FUNDAMENTALS OF BIOCHEMISTRY

sailors. Later, Eijkman (1897), a Dutch physician, found that experimental beriberi could beinduced in hens when fed with polished rice without bran. Such hens could be cured by givingthem the rice polishings. Eijkmann, for a time, believed that the rice polishings contained somethingthat neutralized the beriberi toxin in the polished rice. In 1906, however, Frederick GowlandHopkins ascribed the diseases such as scurvy and rickets to the lack of some ‘dietary factors’. Sixyears later (i.e., in 1912), Hopkins in collaboration with Casimer Funk of Poland, who was

CHRISTIAAN EIJKMAN (LT, 1858-1930)Eijkman, a Dutch physician, was a member of a medical team that was sent tothe East Indies to study beriberi in 1886. At that time, all diseases were thoughtto be caused by microorganisms. When he microoganism that caused beribericould not be found, the team left the East Indies. Eijkman stayed behind tobecome the director of a new bacteriological laboratory. In 1896, he accidentallydiscovered the cause of beriberi when he noticed that chickens being used inthe laboratory had developed symptoms characteristic of the disease. He foundthat the symptoms had developed when a cook had started feeding the chickensrice meant for hospital patients. The symptoms disappeared when a new cookresumed feeding them chicken feed. Later, it was recognized that thiamine(vitamin B1) is present in rice hulls but not in polished rice. For this work, Eijkman shared the 1929Nobel Prize in Medicine or Physiology, with Frederick G. Hopkins.

FREDERICK GOWLAND HOPKINS (LT, 1861-1947)Hopkins, a British biochemist, was born in Eastbourne, East Sussex, Englandon June 20, 1861. He was one of the founders of the science of Biochemistry,which he developed at Cambridge. His greatest work was in the identificationand isolation of vitamins. He shared the 1929 Nobel Prize in Medicine orPhysiology for his discovery of essential nutrient factors now known asvitamins–needed in animal diets to maintain health, along with ChristiaanEijkman of The Netherlands for his discovery of vitamin B1 (thiamine).

Frederick Gowland Hopkins worked out the importance of vitamins inthe diet in the early 1900s. His classic experiment, described in the adjoining

graph, helped people understand the need for vitaminsas additional food factors in a healthy diet.

Basically, he showed that the milk-deficient ratsdid not grow properly. He suggested that the milkcontained an ‘accessory food factor’, or ‘vital amine’–hence the name vitamin, whcih the rats need to stayhealthy. Later work by American researchers showedthis compound to be fat-soluble. We now know thiscompound to be vitamin A.

Hopkins died on May 16, 1947 at Cambridge.

Mea

nb

od

ym

ass/

g

90

80

70

60

50

400 10 20 30 40 50 60

Duration of experiment/days

Group 1

Group 2

Between 1906 and 1912, Hopkins and his team at Cambridge University studied accessoryfood factors. In this experiment two groups of rats are used. Group 1 rats were fed on a dietof purified casein (milk protein), starch, cane sugar, lard and salts. Group 2 rats were fed thesame diet but with a milk supplement.Those on the artificial diet (1) stopped growing and lost body mass; those with the milksupplement (2) grew normally, even though the milk contributed only 4 per cent of the totalfood eaten.

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FAT-SOLUBLE VITAMINS 961working at the Lister Institute of London, suggested thevitamin theory which postulates that ‘specific diseasessuch as beriberi, scurvy and rickets are each caused bythe absence from the diet of a particular nutritionalfactor.’

Funk, for the first time, also isolated the dietaryfactor from rice polishings which acted as antiberiberisubstance. Since this factor was an amine and necessaryto life, Funk at the suggestion of Dr. Max Nierensteinintroduced the term ‘vitamine’ (vitaL = life) to denote it.Since subsequent studies showed that not all these substances are amines, the terminal letter ‘e’was dropped from its spelling at the suggestion of Sir. J.C. Drummond (1919), who also proposedtheir alphabetical nomenclature. In fact, the various vitamins have no structural resemblance toeach other, but because of a similar general function in metabolism, they are studied together.Although these molecules serve nearly the same roles in all forms of life, but higher animals havelost the capacity to synthesize them.

DEFINITIONThe vitamin concept has undergone extensive revisions during the history of biochemistry.

However, Franz Holfmeister’s (LT, 1850-1922) definition— ‘vitamins are substances which areindispensable for the growth and maintenance of the animal organism, which occur both inanimals and plants and are present in only small amounts in food’— still holds good, althoughit has been interpreted in various ways.

Table 33–1. Differences among enzymes, hormones and vitamins

Enzymes

1. These are specific catalyticsubstances.

2. All enzymes are proteinaceousin nature.

3. These are synthesized by theanimal cells.

4. These can initiate and continuereactions.

5. These are not consumed duringgrowth.

6. These are involved incoenzyme syntems.

7. These operate in biologicalsystems.

Examples : Pepsin, Trypsin,Urease, Diastase, Lipase,Catalase, Maltase, Alcoholdehydrogenase, Cytochromeoxidase.

Hormones

These are regulatory substances.

Hormones are steroids (estradiol,testosterone) or peptides (insulin,ocytocin) or amino acidderivatives (thyroxine, adrenalin).

These are synthesized within somepart of the body.

These cannot initiate reactions butcan influence the rate at whichthey proceed.

They are consumed duringgrowth.

These are not involved incoenzyme systems.

Only some hormones are involved in enzyme systems.

Examples: Estradiol, Testos-terone, Relaxin, Progesterone,Insulin, Thyrotropin, Ocyto- cin,Secretin, Intermedin, Thyroxine,Adrenalin.

Vitamins

These are accessory nutrients.

Vitamins belong to diversegroups chemically.

These are not synthesized bymost animal cells but suppliedto the body from outside source(mainly as food). Plants can,however, synthesize them.

—

—

These are involved in coenzymesystems.

Most vitamins are involved inenzyme systems.

Examples : Fat-soluble vitaminsA, D, E, K ; Water-solublevitamins B, C.

CASIMER FUNK (LT, 1884–1967)

Casimer, who was born in Poland,received his medical degree from theUniversity of Bern, and became an U.S.citizen in 1920. In 1923, he returnedto Poland to direct the State Institute ofHealth but returned to the United Statespermanently when World War II brokeout. Funk, in collaboration withHopkins, suggested the vitamin theory.

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The term ‘vitamin’, in its modern sense, usually refers to the substances distinct from majorcomponents of food, required in minute quantities (i.e., oligodynamicin nature) and whose absence causes specific deficiency diseases. Asthe living organisms cannot synthesize most of these compounds, asteady supply of them is sine quo non for life. Their ultimate sourceis the plant or bacterial world.

Differences with hormones— Indeed, for some time, it was believed that the distinction between vitaminsand hormones was no longer tenable. But there exists a fundamental difference between these two classesof active substances : the hormones are regulatory substances whereas the vitamins are accessory nutrients.The vitamins also differ from the hormones in that they are supplied to the body from some external source(i.e., chiefly from the food ingested) whereas the hormones are synthesized within some part of the bodyof an organism. Moreover, most vitamins and some hormones are involved either directly or indirectly inenzyme systems in order to carry out biochemical functions. Some vitamins are also known to be coenzymes.

A comparison of enzymes, hormones and vitamins is presented in Table 33–1.

GENERAL CHARACTERISTICS

The vitamins are characterized for some general facts, which are listed below :1. Vitamins are of widespread occurrence in nature, both in plant and animal worlds.2. All common foodstuffs contain more than one vitamin.3. The plants can synthesize all the vitamins whereas only a few vitamins are synthesized

in the animals.4. Human body can synthesize some vitamins, e.g., vitamin A is synthesized from its

precursor carotene and vitamin D from ultraviolet irradiation of ergosterol and 7-dehydrocholesterol. Some members of the vitamin B complex are synthesized bymicroorganisms present in the intestinal tract. Vitamin C is also synthesized in someanimals such as rat.

5. Most of vitamins have been artificially synthesized.6. All the cells of the body store vitamins to some extent.7. Vitamins are partly destroyed and are partly excreted.8. Vitamins are nonantigenic.9. Vitamins carry out functions in very low concentrations. Hence, the total daily requirement

is very small.10. Vitamins are effective when taken orally.11. Synthetically-made vitamins are just as nutritionally good as natural vitamins.12. Old people need about the same amounts of vitamins as young people.

CLASSIFICATIONIn 1913, McCollum and Davis described a lipid-soluble essential food factor in butter fat and

egg yolk. In 1915, a water-soluble factor in wheat germ necessary for the growth of young ratswas also described. Since then, two categories of vitamins are usually recognized : fat-soluble andwater-soluble. These two groups discharge rather different functions.

A. Fat-soluble vitamins. These are oily substances, not readily soluble in water and theirbiochemical functions are not well understood. They contain only carbon, hydrogen and oxygen.Their examples are vitamins A, D, E and K. They, however, play more specialized roles in certaingroup of animals and in particular type of activities. For instance, they function in the formationof a visual pigment (vitamin A), in the absorption of calcium and phosphorus from the vertebrateintestine (vitamin D), in protecting mitochondrial system from inactivation (vitamin E) or in theformation of a blood clotting factor in vertebrates (vitamin K). The individual fat-soluble vitaminsbear a closer resemblance to each other chemically. In fact, the 4 fat-soluble vitamins can beregarded as lipids. Vitamins A, E and K are terpenoids, and vitamin D is a steroid. All four are

Sine quo non is a Latinphrase, which means anindispensable condition.

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isoprenoid compounds, since they are synthesized biologically from units of isoprene (for structure,refer page), a building block of many naturally-occurring oily, greasy or rubbery substances ofplant origin. Unlike the water- soluble vitamins (B and C), fat-soluble vitamins can be strored inthe body, e.g., an adult's liver can store enough vitamin A to last several months or longer.However, because fat-soluble vitamins are storable, their excessive intakes can result in toxicconditions (hypervitaminoses).

B. Water-soluble vitamins. Most of these are universally vitamins since they perform thesame general functions wherever they occur. Besides C, H and O, they also contain nitrogen. Theyare catalytic factors and as such form vital links in the chains of biochemical reactions characteristicof all living objects. For instance, thiamine is required whenever sugars are oxidized aerobicallyto release energy. The individual water-soluble vitamins bear no closer resemblance to each otherchemically. The biochemical or coenzyme function of nearly all of these is known. The commonwater-soluble vitamins are vitamins of B complex such as B1 through B12

(vitamins B4, B8, B10

and B11, however, do not exist) and the vitamin C. Choline, inositol, p-aminobenzoic acid,bioflavonoids and α-lipoic acid are frequently included in this category. Many nutritionists, however,do not consider them as true vitamins, although their dietary deficiencies in animals lead to thedevelopment of characteristic symptoms. Moreover, none of them except α-lipoic acid is a partof the coenzyme system. The B-series of vitamins, being water-soluble and excretable, are requireddaily in meagre amounts (in milligrams or even less) for the normal growth and good health ofhumans and many other organisms. It is virtually impossible to ‘overdose’ on them.

STORAGE OF VITAMINS IN THE BODY

The vitamins can be stored in the body to a slight extent. The liver cells are, however, richin certain fat-soluble vitamins. For instance, the amount of vitamin A contained in the liver issufficient enough to meet its requirement without any additional intake for about 6 months. Similarly,the quantity of vitamin D stored ordinarily in the liver is sufficient to maintain a person withoutany additional intake of vitamin D for about 2 months. The storage of vitamin K is, however,relatively slight.

The water-soluble vitamins are stored even in lesser amounts in the cells. Evidently, in casesof deficiency of vitamin B compounds, clinical symptoms appear rather early, that is within a fewdays. Similarly, absence of vitamin C can induce deficiency symptoms within a few weeks. VitaminC is stored in the adrenal cortex.

DAILY HUMAN REQUIREMENTS OF VITAMINSThe requirement of vitamins varies considerably depending on the nature of the individual

consuming them. Some general facts regarding vitamin requirement may be listed below :

1. Greater the size of the individual, higher are his vitamin needs.

2. Younger ones require higher quantities of vitamins than do the elders.

3. The vitamin requirements increase when a person performs exercise.4. During ailments, the vitamin requirements are ordinarily enhanced.

5. Under certain specific conditions of metabolic disorders when the vitamins cannot beproperly utilized, the requirement for one or more specific vitamins is at extreme.

6. Growing children require comparatively high quantities of vitamin D.7. During pregnancy and lactation, the vitamin D requirement by the mother is greatly enhanced.

8. The requirements of vitamin B complex (esp., that of vitamin B1) are increased underconditions of greater utilization of carbohydrates.

Contents


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Contents


The daily requirement of any vitamin (refer Table 33–2) for any individual is not a fixedquantity and varies according to the rate of metabolism. In general, in all cases of high metabolicactivity (such as heavy muscular work, during pregnancy and lactation and in growing children),the vitamin requirement is proportionately high. Normally, a man doing ordinary work can obtainenough vitamin from his balanced diet.

The intestinal organisms may synthesize vitamins in significant amounts and play a vital rolein regulating the quantity of vitamin available to the organism. Most of the vitamins of B complexgroup (such as thiamine, riboflavin, nicotinic acid, pyridoxine, biotin, folic acid) and vitamain Kare some of the vitamins synthesized by the intestinal organisms. These may be absorbed tovarying extents and utilized. This fact renders rather ‘inaccurate’ the figures for daily requirementof the various vitamins. Certain organisms, however, destroy vitamins. Supplementing the diet withcertain antibiotics and sulfa drugs enhances the growth of these organisms.

In measuring human requirements of vitamins, certain units have been used. In the beginning,these were arbitrarily fixed and were mainly based on the amount necessary to check avitaminosisin animals under standard conditions. With the passage of time, the various vitamins were synthesizedand so it became possible to base the unit on the weight of purified preparations.

AVITAMINOSES(Deficiencies of Vitamins)

A lack of one or more vitamins leads to characteristic deficiency symptoms in man. Multipledeficiencies caused by the lack of more than one vitamin are, however, more common in humanbeings. Vitamin deficiencies occur rather frequently in certain parts of the world for socioeconomicreasons. Avitaminosis may be of following 2 types :

A. primary or direct— This arises due to inadequate intake of vitamins resulting fromchronic alcoholism, dietary fads etc.

B. secondary or ‘conditioned deficiency’— This arises due to other factors such asmalabsorption, increased excretion, allergies, anorexia, gastrointestinal disorders etc.

Vitamin deficiency, whether primary or secondary, leads to:

(a) a gradual decrease in tissue levels of the vitamin(s) deficient,

(b) a biochemical lesion,(c) an anatomic lesion, and

(d) finally cellular pathology and disease.

This sequence is schematically represented in Fig. 33–1.

Fig. 33–1. Sequence of events occurring in a tyical avitaminosis

An account of fat-soluble vitamins is given below.

s

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VITAMIN AA. History. It was first recognized as an essential nutritional factor by Elmer McCollum in

1915 and then isolated from fish-liver oil by Holmes in 1917. On account of its established rolein the visual process, it is often called as antixerophthalmic factor or the “bright eyes” vitamin.It was first synthesized in 1946 by Milas.

B. Occurrence. Liver oils of various fishes are the richest natural sources of vitamin A. Sharkand halibut contain maximum amount whereas the cod-liver has lowest amount. Depending uponthe species of fish and the time of year of catch, the fish livers contain 2,000 to 100,000 I.U. pergram of vitamin A. The amount present in human liver is much less (500 to 1,000 I.U.per gram).However, polar bear liver is an extremely concentrated source of vitamin A. Other noteworthysources are butter, milk and eggs and, to a lesser extent, kidney. In its provitamin form (i.e., ascarotenes) it is supplied by all pigmented (particularly yellow) vegetables and fruits such ascarrots, pumpkins, cantaloupes, turnips, peppers, peas, sweet potatoes, papayas, tomatoes, apricots,peaches, plums, cherries, mangoes etc. Yellow corn is the only cereal containing significant amountsof carotene. New-born infants have low quantities of vitamin A content that is rapidly augmentedbecause colostrum and breast milk furnish large amounts of the vitamin. The milk of well-fedmothers, however, contains sufficient amounts of vitamin A (in ester form) for the infant's need.However, vitamin A is absent from vegetable fats and oils (olive oil, linseed oil, groundnut oil).It is added to margarine during its manufacture from these oils.

The β-carotene content of some items are presented in Table 33–3.

Table 32–3. β β β β β-carotene content of some fruits and vegetables

Fruit/vegetable β–carotene(µg/100 g)

Mango (ripe) 300Orange 210Tomato 190Drumstick leaves 7,000 – 8000Coriander leaves 7,000Carrot 1,500 – 3,000Radish leaves 3,600Mint leaves 1,800Cabbage 1,300

Table 33–1. presents vitamin A content of some animals including those of polar regions andfishes.

Table 33-1. Vitamin A content of some animal foods

Source Biological Name Vitamin A

(I.U./g of food)

Weddel seal Leptonychotes weddelli 444Ox liver* 550Cod liver* 600Southern elephant seal Mirounga leonina 1,160Antarctic husky Canis familiaris 10,570Halibut liver oil* 30,000Arctic bearded seal Erignathus barbatus 12,000 – 14,000Polar bear Thalarctos maritimus 24,000 – 35,000

* Commonly recommended as source of vitamin A

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Vitamin A originates in marine algae, and then passes up the food chain to reach the largecarnivorous animals. Toxic levels of vitamin A may accumulate in the livers of a wide range ofcreatures such as Polar bears, seals, porpoises, dolphins, sharks, whales, Arctic foxes and huskies.Even a small meal of southern Australian seal liver, say 80g, may produce illness in man. Mostof the foods recommended as source of vitamin A contain well below the toxic levels of vitaminA, but one– Halibut liver oil– contains dangerously high amounts of vitamin A.

As regards the vitamin A contents of polar animals, one can see that, in reality, very littlequantities of livers of these animals are required to kill a human being : 30–90 g of polar bear liveror halibut liver, 80–240 g of bearded seal liver and 100-300 g of Antarctic husky liver is enoughto kill a human being.

C. Structure. Vitamin A is found in two forms A1 and A2. The carotenoids that give rise tovitamin A in animal body is named as provitamin A. These inculde α-, β- and γ-carotenes andcryptoxanthin. β-carotene is most potent of all these forms. A molecule of β-carotene is made ofeight 5-carbon isoprenoid units, linked to form a longchain of 40 carbon atoms with an ionone ring at eachend. It is an orange-red hydrocarbon and uponhydrolysis yields 2 moles of vitamin A1 (Fig. 33–2).During hydrolysis, a cleavage occurs at the mid pointof the carotene in the polyene chain connecting the 2β-ionone rings. This conversion usually takes place in livers of fishes and mammals. Vitamin A1is a complex primary alcohol called retinol, having the empirical formula, C20H29OH. The terminalhydroxyl group is ordinarily esterified. It contains β-ionone ring.

Fig. 33–2. Hydrolysis of βββββ-carotene

Another form of vitamin A, present in fresh-water fishes, is known as vitamin A2 (Fig. 33–3). Itdiffers from vitamin A1, which is found in salt-water fishes, in possessing an additional conjugatedouble bond between carbon atoms 3 and 4 of the β-ionone ring. Its potency is 40% that ofvitamin A1.

ααααα- and γγγγγ-carotenes as well ascryptoxanthin, however, yield only 1molecule of vitamin A since in themone of the two rings present in theirmolecule differs in structure from thatof vitamin A.

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Fig. 33–3. Vitamin A2 or 3-dehydroretinol

(all trans)

D. Properties. Ordinarily retinol is a viscid, colourless oil but by careful fractionation it hasalso been isolated as pale yellowish needles. It gives a characteristic absorption band in ultraviolet(UV) spectrum at 328 mµ. It is soluble in fat and fat solvents but insoluble in water. Loss ofvitamin A in cooking, canning and freezing of foodstuffs is small; oxidizing agents, however,destroy it. It is destroyed on exposure to UV light. Vitamin A is relatively unstable in air unlessprotected by antioxidants including vitamin E.

E. Metabolism. In the tissues, the metabolic transformation of retinol is carried out by enzymes.The dietary β-carotene is split into retinal (Fig. 33–4) by an enzyme of the intestine. Retinal is

Fig. 33–4. Formation of retinoic acid

(Adapted from Ganguli J, 1973)

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then reduced by another enzyme to retinol which, in turn, is converted to retinyl ester by reactingwith a fatty acid like palmitic. The retinyl ester, on the contrary, is enzymatically hydrolyzed toproduce retinol which is re-esterified with palmitic acid to produce retinyl ester. This is absorbedthrough the lymphatic system and is stored in the liver.

Liver stores vitamin A in large quantities mainly in the form of retinyl ester. But the vitaminA that circulates in the blood is in the form of retinol and is bound to a specific carrier proteincalled retinol binding protein (RBP). The retinyl ester present in the liver, therefore, has to beconverted to retinol before it mixes with the blood. Liver can also successively convert retinol toretinal and retinal to retinoic acid. Retinoic acid is quickly absorbed from the intestine through theportal system and is rapidly excreted back into the intestine through the bile.

Vitamin A helps maintain the epithelial cells of the skin and the linings of the digestive,respiratory and genito-urinary systems. These linings play a protective role against cancer-causingagents (or carcinogens), viruses and bacteria and are rendered vulnerable by a deficiency ofvitamin A. Vitamin A guards against cancer by protecting cell walls from undesirable oxidation,and scavenging the products of oxidation— free radicals, which are linked to the development ofcancer.

F. Deficiency. Vitamin A is perhaps the most important as it affects the various metabolicprocesses in the body. It has profound effect on epithelial structures, in general. Vitamin Adeficiency leads to the onset of many diseases like nyctalopia or night blindness (inability to seein night), xerophthalmia (scaly condition of the delicate membrane covering the eyes), keratomalacia(softening of the cornea), phrynoderma or “toad skin” (hard and horny skin) and stunted growth.

Xerophthalmia or xerosis is a major cause of blindness in childhood and is still a majorhealth problem in Far East such as Hong Kong, Jakarta, Manila and Dhaka. The disease affectslarge number of children but few adults. Xerophthalmia is characterized by drying of the eyes andhence so named (xerosG = dry ; ophthalmosG = eyes). The lacrymal glands become stratified andkeratinized and cease to produce tears. This makes the external surface dry and dull. The ulcersdevelop. The bacteria are not washed away. The eyelids swell and become sticky. This results infrequent exudation of blood, causing severe infection to the eye. If left untreated, blindness results.Incredible, yet true, about 1400 cases of xerophthalmia were reported in 1904 among Japanesechildren. Besides, during World War I, many xerophthalmic cases were reported in Denmarkbecause of the fact that butterfat was shipped out of that country in huge quantities and people hadto live on substitutes with no retinol.

Keratomalacia (keratoG = hair ; malakiaG = softness) is a corneal disease, occurring maximallyin pre-school children of 3–4 years. This usually happens suddenly in young children withkwashiorkor esp., after an episode of diarrhea or infection. At first the cornea loses its lustre,undergoes a necrosis and develops a few pin-point ulcers, which later coalesce to form a large,white ulcerative area. The perforation of the cornea may follow sometime, causing the release ofaqueous humour and prolapse of the iris. Occasionally, instead of extensive ulceration and perforationof the cornea, the whole eyeball may shrink. Keratomalacia is unfortunately still prevalent on awide scale in many parts of India (South and Eastern) and Indonesia and some other countries ofAsia and Africa.

Phrynoderma is a skin lesion and is characterized by follicular hyperkeratosis. In it, the skinesp., on the outer aspects of forearms in the regions of the elbows and of the thighs and buttocksbecomes rough and spiky. In severe cases, the trunk is also affected.

Also, the damaged epithelial structures in diverse organs such as the eyes, the kidneys or the

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respiratory tract often become infected. It is for this reason that vitamin A has been called an‘anti-infection’ vitamin. The vaginal epithelium may become cornified, and epithelial metaplasiaof the urinary tract may contribute to pyuria and hematuria. Increased intracranial pressure withwide separation of cranial bones at the sutures may occur.

In the alimentary tract, the deficiency of vitamin A causes damage to the intestinal mucosa,resulting in diarrhea.

Vitamin A is an important factor in tooth formation. In its deficiency, there is a defectiveformation of enamel so that the dentin is exposed. Evidently, sound tooth formation does not occur.Vitamin A deficiency may result in retardation of mental and physical growth and in apathy.Anemia with or without hepatosplenomegally is usually present.

Other deficiency diseases that have been attributed to vitamin A are atrophy of the testes anddisturbances of the female genital organs.

According to a report, presented at a meeting of the National Seminar on Corneal Disastersheld in New Delhi (1981), India accounts for about one-third of the total blind population of theworld, that is about 9 million blind people and that every year about 25,000 children go blind inIndia due to malnutrition.

Researches conducted by the National Institute of Nutrition (NIN), Hyderabad (1978), showthat about 30% of the blind in India lost their sight before they were 21. NIN studies have alsorevealed that about 10% of the school children belonging to the poorer socioeconomic groupsshow signs of vitamin A deficiency. It is however, worth-mentioning that the vitamin A deficiencyis mainly a result of ignorance rather than the non-availability of food or of the resources to acquirethe food as is the case with protein calorie malnutrition. According to NIN researches, if 40 g ofgreen leafy vegetables are included in the existing diet without any other changes, the child willget the necessary vitamin A.

G. Hypervitaminosis A. Vitamin A is less toxic to man and other animals when it is takenin large doses over a long period of time. The children receiving overdosages of 500,000 units ofvitamin A per day exhibit tender swellings over the bones, limited motion and definite hyperosteoses.

Human adults consuming 500,000 units or more show nosebleed, weakness, headache, anorexiaand nausea. Continuous excessive intake of the vitamin is dangerous because it results in fragilebones and abnormal fetal development. In the case of plant carotenoids, a dietary oversupply (forexample, eating too many carrots on a daily basis) results in carotenosis, a condition readilydiagnosed by yellowing of the skin. These toxic effects develop presumably due to the fact thatviatmin A, like vitamin D, is not readily excreted and consequently tissue levels may build updangerous concentrations.

H. Human requirements. The recommended dietary allowance (RDA) of vitamin A is about5,000 International Unit (I.U.). Growing children, adults and pregnant and lactating mothersrequire high doses of up to 8,000 I.U. It is also possible that some individuals require more thanthe minimal requirement due to either faulty absorption or some other reason. For vitamin A, theWorld Health Organization (WHO) has chosen as one International Unit the biologic activity of0.000344 mg (0.344 µg) of synthetic vitamin A-acetate, which is equivalent to 0.30 µg of retinol.In fact, one µg of β-carotene, the provitamin form, getsconverted to about 0.167 µg of retinol, the true vitaminform. Another way of putting it is that the retinol equivalentof 1 µg of β-carotene is 0.167. A diet consisting of 1/2pint of milk, 1 ounce of butter and an adequate amount of

1 pint = 0.568 litre (British Units) = 0.473 litre (U.S. Units)1 ounce = 27.09 gm

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green vegetables or carrots daily is sufficient enough to meet minimal requirement. The optimalrequirement of this vitamin is met with by taking 1 pint of milk and cod liver oil daily.

Fatality Due to Exessive Intake of Vitamin A

A three-man team of explorers from the Australasian Antarctic Expedition started theirexpedition to explore Antarctica in January, 1912. The team was led by DouglasMawson and the other two members were Lt. BES Ninnis and Xavier Mertz, a Swissscientist. Disaster struck on December 14, 1912, when Ninnis fell into a very deep pitand died. With him also went precious food supplies. With most of their food gone,Mawson and Mertz decided to return to their base at Commonwealth Bay, which is atthe shores of Antarctica. From here, they could take the ship back to their country. ButCommonwealth Bay was about 315 miles from where they were stationed. Coveringthat distance in the inhospitable surroundings of Antarctica would have taken themweeks, and they had only 10 days’ food left with them. They had 6 huskies with them(Huskies are Eskimo dogs, used as ponies in Antarctic region). Both knew that sooneror later they would have to eat those dogs to remain alive.

So they did kill the huskies and ate their flesh, but the flesh was stringy (i.e., fibrous)and they could not eat it. But they found the liver softer and easier to eat, so they tookgenerous quantities of liver. Mertz was a near vegetarian; he could not eat the stringyflesh, so he took more liver than Mawson. Little did he realize that he was taking fatalamounts of vitamin A in this form. On New Year’s Eve, Mertz began to feel ill. Nextday, he complained of stomachache. Few days later, both men began displaying typicalsymptoms of vitamin A poisoning, although Mawson was affected less. Their skin wasfalling off their bodies in strips and their hair was dropping out in handfuls. A weeklater, Mertz fell into a delirious sleep and never woke. His was the first known caseof death due to overdose of vitamin A. Mawson, however, survived, and ultimately didreturn to Commonwealth Bay.

I. Treatment. For xerophthalmia, the treatment consists in giving 1,500 µg/kg/24 hr ofvitamin A orally for 5 days and then continued with intramuscular injection of 7,500 µg ofvitamin A in oil daily until recovery occurs.

J. Vitamin A and the vision. George Wald (Nobel Laureate, 1966) of Harvard Universityhas made major contributions to our understanding of the role of vitamin A in visual process. Theretina of the human eye contains 2 types of receptor cells, rods and cones. Animals which havevision only in bright light (“day vision”) like pigeons have only cones while animals which cansee in night or dim light (“night vision”) like owls have only rods. Thus, the rods are concernedwith seeing at low illumination and the cones are responsible for colour vision.

I. Rod vision. The rods contain a photosensitive visual pigment known as rhodopsin. It isa conjugated protein and upon illumination splits into a protein called opsin and a carotenoidcalled retinene1 (Fig. 33–5). It is actually this reaction which may initiate an enzymic reactionresponsible for visual mechanism. The retinene1, released by bleaching of rhodopsin, is reducedto vitamin A1 by NADH in the presence of retinene1 reductase, an enzyme present in the retina.Vitamin A1 of mammals is in all-trans form like the retinene liberated by bleaching rhodopsin.The isomerization of all-trans retinene1 and vitamin A1 to ∆”-cis forms is catalyzed by the enzymeretinene isomerase. The major site of this reaction is the liver. Opsin in dark reacts with ∆”-cisretinene1 to regenerate rhodopsin. The series of reactions leading from vitamin A1 to rhodopsinconstitutes the major events in ‘dark adaptation’. And the reactions leading to bleaching ofrhodopsin constitute what is known as ‘light adaptation’.

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Fig. 33–5. Visual cycle in vertebrates.

Whereas the retina of mammals, birds, frogs and marine fishes contain rhodopsin, all fresh-water fishes have another visual pigment porphyropsin in their retina. Wald has shown thatporphyropsin undergoes the same cyclic changes on bleaching and regeneration as in the case ofrhodopsin except that here retinene A2 and vitamin A2 come in picture.

II. Cone vision. According to Young-Helmholtz trichromatic theory, there are present at least3 closely related pigments in cones. These are iodopsin, chlorolabe and erythrolabe. The last twopigments absorb actively in the green and the red portions of the spectrum respectively. When lightstrikes the retina, it bleaches one or more of these pigments based upon the quality of light. Thepigments are converted to all-trans retinene and the protein, opsin. This reaction produces thenerve impulse which is read as blue, green or red based on the pigment affected.

VITAMIN DA. History. The first demonstration of the existence of vitamin D was shown by Elmer

McCollum in 1922 who found that cod liver oil was effective in preventing rickets, a diseaseinduced in rats by providing low calcium diet. On account of its preventive action on rickets,vitamin D is often called as antirachitic factor. It is also known as ‘sunshine vitamin’ as itsprovitamin form present in human skin is easily convertedto the active form by irradiation with ultraviolet light. Atleast 10 different compounds are known to have antirachiticproperties and are designated as D2, D3 etc, but the two,namely, vitamin D2 (ergocalciferol) and vitamin D3(cholecalciferol) are more important. Vitamin D3 was, however,first isolated by Brockmann and others.

B. Occurrence. The best natural sources of vitamin D are the liver oils of many fishes suchas cod and halibut. The flesh of oily fishes (e.g., sardine, salmon, herring ) is also excellent source.Egg yolks are fairly good but milk, butter and mushrooms are poor. The diets of infant maycontain only small amounts of vitamin D; cow’s milk contains only 0.1 to 1 µg/quart (1 µg = 40IU). Cereals, vegetables and fruits contain only negligible amounts. Eggs and yolks contain 3to 10 µg/g. Most marketed cow’s milk is fortified with 10 µg of vitamin D per quart and mostcommercially–prepared milks for infant formulae are also fortified. Vitamin D2 is of plant originand is produced commercially by irradiation with ultraviolet light of a provitamin known asergosterol which is found in plants, especially in ergot (hence so named) and yeast. Vitamin D3,

The designation D1 is not used,however, because D1 was thedesignation for the first crystallinematerial, which later turned outto be a mixture.

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on the contrary, is of animal origin and can be produced from 7-dehydrocholesterol also byirradiating with ultraviolet light. The 7-dehydrocholesterol is also a provitamin found naturallyoccurring in animals. Vitamins D2 and D3 both have about the same degree of activity in thehuman beings. In nature, these vitamins occur as esters. Like vitamin A, vitamin D is absent fromvegetable fats and oils and is added to margarine during its manufacture.

C. Structure. The transformation of ergosterol (C28H44O) to the active form D2 takes placethrough a series of intermediate steps illustrated as below :

Ergosterol → Lumisterol → Protachysterol → Tachysterol → Precalciferol

→ Calciferol

Similarly, cholecalciferol (C27H44O) is produced from 7-dehydrocholesterol through a seriesof intermediaries as follows :

7-dehydrocholesterol→ Lumisterol3 → Tachysterol3 → Precalciferol3 → Cholecalciferol

During the activation of the provitamins, the ring B is cleaved between carbon atom 9 and10 to produce vitamins D2 and D3 (Fig. 32–6).

Fig. 33–6. Activation of provitamins of the vitamin D group

Note that in both the cases, the effect of irradiation is the opening of ring B.

It may, however, be noted that the two vitamins, D2 and D3 and also D4 and D5 (Fig. 33–7),differ only in their side chains attached to C17.

ToxisterolSuprasterols

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Fig. 33–7. Side chains of vitamins D4 and D5

Other forms of vitamin D may be obtained by irradiation of other sterols. Vitamin D4, forexample, is produced by irradiation of 22-dihydroergosterol. Its potency is 50—70% that ofvitamin D2.

However, researches conducted by DeLuca et al (1968) indicate that the biologically activeform of vitamin D3, present in animals such as rat, has a slightly different structure. It is identifiedas 25-hydrocholesterol (Fig. 33–8). It is a more polar compound and has an additional OH groupat C25. It is one and a half times more potent than the vitamin in curing ricket. Also, it stimulatesbone metabolism and intestinal calcium transport more rapidly than the vitamin. It is synthesized

Fig. 33–8. Side chain of 25-hydrocholesterolor 25–hydroxycholecalciferol

in the liver and is then converted into 1,25-dihydroxycholecalciferol [1,25(OH)2D3] in the kidneys.Cholecalciferol and its derivatives are seco-steroids, i.e., ring A is not rigidly fused to ring B.Because of its conformational mobility, ring A of a seco-steroid exists in two equilibrated conformers.Now as the in vitro mode of action of vitamin D is understood, it has been proposed that 1,25(OH)2D3

is actually a hormone and not a vitamin as it fits the traditional description of a hormone.1,25(OH)2D3 is produced in the kidneys (organ) and transported by the blood to intestinal mucosaand bone (target tissues), where it functions in the processes for the absorption, reabsorption andmobilization of calcium and phosphate ions. In conjunction with parathormone and calcitonin, ithas a major role in homeostasis of Ca and P in the body’s fluids and tissues. Now because ahormone-receptor protein has been identified for 1,25(OH)2D3, the status of vitamin D as ahormone is well established.

D. Properties. Vitamin D is a white and almost odourless crystalline substance, soluble in fatand fat solvents. It is fairly heat resistant and also relatively resistant to oxidation. It is not affectedby acids and alkalies.

E. Metabolism. The provitamin D3 can be synthesized within the human body so that it may,in fact, not be required in the diet. This may, henceforth, not be treated as a vitamin. In the pastwhen man lived mainly outdoors and with minimum clothing, there was no hindrance for thepenetration of ultraviolet light from the sun to convert it into the active form. In the far northernareas, however, the amount of light is not adequate for conversion and as such fish liver oils serveas excellent source of vitamin D in these areas. The increased need of this vitamin is usually feltin growth and in pregnancy to provide for the needs of the foetus.

Vitamin D plays an important role in calcification of bones and teeth. It encourages theabsorption, into the blood, of calcium salts and phosphates. Calcium passage across duodenumoccurs mainly by diffusion and active transport of Ca2+ occurs across the ileal mucosa. Both theseprocesses are related in dificiency of vitamin D. The subsequent release of bound calcium is also

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markedly stimulated by vitamin D but only in the presence of parathyroid hormone. On the whole,the function of vitamin D is to cause increased absorption, longer retention and better utilizationof calcium and phosphorus in the body.

There is considerable difference in the potency of these 2 common forms of vitamin D. Forexample, vitamin D2 is a powerful antirachitic agent for man and for the rat but not for thechicken. Vitamin D3, on the contrary, is much more potent for the chicken than either for man orthe rat.

F. Deficiency. The most characteristic symptom of vitamin D deficiency is the childhooddisease known as rickets. Deficiency of it in human adults leads to osteomalacia, a condition thatmight also be termed “adult rickets”.

Rickets (derived from an old English word,wrickken = to twist) is primarily a disease ofgrowing bones. In it, the deposition of inorganicmaterials on the matrix of bones (i.e., calcification)fails to occur, although matrix formation continues.Rickets is unusual below the age of 3 months (mo).It may occur in older children with malabsorption.Clinical manifestations of rickets in childrenusually manifest in the first year or in the secondyear. One of the early signs of rickets iscraniotabes, which is due to thickening of theouter table of the skull and is detected by pressingfirmly over the occiput or posterior parietal bones.A ping-pong ball like sensation will be felt.Craniotabes near the suture line may, sometimes,be present in normal premature infants.Costochondral junctions become prominent to give appearance of a beaded ribs, the rachiticrosary. Thickening of the wrists and ankles are other early evidences of osseous changes.Increased sweating, especially around the head, may also be present.

Signs of advanced rickets are easily identified. These are listed below :1. Head : Craniotabes may obliterate before the end of the 1st year, although the rachitic

process continues. The softness of the skull may result in flattening and, at times, permanentasymmetry of the head. The anterior fontenel is larger than normal; its closure may be delayeduntil after the 2nd year of life. The central parts of the parietal and frontal bones are usuallythickened, forming prominences or bosses, which give the head a box-like appearance (catputquadratum).

2. Thorax : The sides of the thorax become flattened, and the longitudinal grooves developposterior to the rosary. The sternum with its adjacent cartilage projects forward leading toprotruding chest (pigeonbreast). Along the lower border of the chest develops a horizontaldepression (Harrison groove), which corresponds with the costal insertions of the diaphragm.

3. Spinal cloumn : Moderate degree of lateral curvature (scoliosis) is common and akyphosis (=increased convexity in the region of thoracic spine) may appear in the dorsolumbarregion when sitting. Lordosis (=forward curvature of the lumbar spine) may be seen in the erectposition.

4. Pelvis : The pelvic entrance is narrowed by a forward projection of the promontory; theexit, by a forward displacment of the caudal part of the sacrum and coccyx. In the female, thesechanges, if they become permanent, add to the hazards of childbirth and necessitate caesareansection.

CLINICAL IMPLICATIONSRICKETS

As described by Daniel Webster in 1645, inrickets, “ ........ the whole bony structure isas flexible as softened wax, so that the flaccidand enervated legs can hardly support thesuperposed weight of the body ; hence thetibia, giving way beneath the overpoweringweight of the frame, bend inwards ; and forthe same reason the legs are drawn togetherat their tops ; and the back, by reason of thebending of the spine, sticks out in a humpin the lumbar region ........ the patients intheir weakness cannot (in the most severestages of the disease) bear to sit upright,much less stand .....”.

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5. Extremities : The epiphyseal enlargement at the wrists and ankles becomes morenoticeable. Bending of the softened shafts of the femur, tibia and fibula results in bowlegs (knock-knees) ; the femur and the tibia may also acquire an anterior convexity. Coxa vara is sometimesthe result of rickets.

Deformities of the spine, pelvis and legs results in reduced stature, rachitic dwarfism.

6. Ligaments : Relaxation of ligaments helps to produce deformities and partly accountsfor knock-knees, weak ankles, kyphosis and scoliosis.

7. Muscles : The muscles are poorly developed and lack tone. As a result, the rachiticchildren are late in standing and walking. Abdomen becomes protuberant (potbelly) because ofmarked hypotonia of abdominal wall muscles, visceroptosis and lumbar lordosis.

8. Sense organ : Avitaminosis D in early infancy results in bilateral lamellar cataracts.

9. Dentition : Eruption of temporary teeth may be delayed in rachitic children. The firsttooth in such babies appears between 6th and 9th month, at which time it has appeared in half ofthe normal babies. In deficiency of vitamin D, the formation of teeth becomes defective and leadsto the development of dental caries.

Chemical analysis of the bones of rachitic children reveals the presence of low inorganic andhigh organic and water contents in them. The ratio of calcium to phosphorus (C/P), however,remains constant. In the blood serum, there is usually a normal content of calcium but the phosphatecontent is reduced (1.5–3.5 mg/dL), against a normal value of 4.5–6.5 mg/dL in healthy infants.Vitamin D deficiency is also accompanied by generalized aminoaciduria, a decrease of citrate inbone and its increased urinary excretion, decreased ability of the kidneys to make an acid urine,phosphaturia, and, occasionally, mellituria. The parathyroid glands hypertophy in rickets.

Rickets in itself is not a fatal disease but complications and intercurrent infections such aspneumonia, tuberculosis, and enteritis are more likely to cause death in rachitic children than innormal children.

Rickets is most prevalent where climate or custom prevents individuals from exposure to sun,whereby checking vitamin D production by irradiation of the skin. In the seventeenth century. thisdisease was so common in England that it used to be known as “English disease”. A studyconducted by the Indian Social Institute, New Delhi (1981) shows that about 168 children per1,000 of live births die of rickets in India.

In osteomalacia (osteonG = bone ; malakiaG = softness), the action of bones is essentially likethat in rickets. However, the bones become softer than the rachitic bones and the C/P ratio doesnot remain constant. The loss of calcium is greater than that of phosphorus and there is a relativegain in magnesium content. The disease is prevalent in India, China and Arab, particularly amongwomen because of the custom that keeps them indoor and also prevents them from exposure to sun.This is particularly true of Bedouin Arab women who are clothed so that only their eyes areexposed to sunlight. The serum calcium is reduced, sometimes to such an extent that tetanydevelops.

Vitamin D3 deficiency also leads to a disease called idiopathic steatorrhea or celiac disease.Like osteomalacia, the disease is characterized by demineralization of the bones which may resultin deformities or dwarfism. In fact, celiac disease is indirectly a vitamin D deficiency because theprimary abnormality appears to be, in part, a fatty diarrhea. The fat is not absorbed in the intestineand is passed out in stool along with calcium salts and vitamin D.

G. Hypervitaminosis D. Overdosing of calciferol to the children and adults as well producesdemineralization of bone. Serum concentrations of both calcium and phosphate are greatly raised,resulting in metabolic calcification of many soft tissues and the formation of renal calculi. Thelatter disorder may block the renal tubules causing hydronephrosis.

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The use of very high doses of vitamin D is not danger-free, however. The toxic effects causedby excess dosage include anorexia, nausea, polyuria, weakness, headache etc. The toxicity is dueto the diminished excretion of this vitamin, rather than its storage in the liver. The water-solublevitamins, on the contrary, if given in excess pass out immediately in the urine and are henceforthnontoxic. Much of the whole milk available in urban areas and evaporated milk are fortified withvitamin D concentrate so that 1 quart of fresh, whole milk or a cane of evaporated milk containsthe required amount (i.e., 10 µg).

H. Human requirements. Vitamin D requirement is greatly influenced by the amount ofultraviolet light to which the individual is exposed. Half an hour of direct sunlight on the cheeksof a baby each day is sufficient to generate the minimal daily requirement of vitamin D. For adultsalso, exposure to sunlight for 30 minutes a day is believed to satisfy the daily requirement (about10 µg or 400 IU) of vitamin D. As effective UV rays do not penetrate glass windows, exposureto sun through window glass is of little importance. Smoke also hinders the progress of these raysand as such city sunshine is not much beneficial. It is for these and some other reasons that vitaminD should be included in the diet. This is particularly true for older people. The recommended dailyallowance of vitamin D is 400 I.U. for infants, pregnant women and lactating mothers. For adults,400 units are adequate. One International Unit is defined as the biologic activity of 0.025 µg ofpure crystalline vitamin D3.

VITAMIN EA. History. The presence of this active principle was first demonstrated in vegetable oils by

Evans and Mattill independently in 1920. This was designated as vitamin E or antisterility factoron account of the development of sterility in animals in its absence. In 1936, two compounds withvitamin E activity were isolated from wheat germ oil by Evans and his associates and given thename, α- and β-tocopherol (tokosG = childbirth ; pherosG = to bear; ol = an alcohol). Subsequently,five other tocopherols were obtained from various cereal grains like wheat germ, corn oil, rice etc.

B. Occurrence. The tocopherols are of widespread occurrence in many plant oils such aswheat germ, rice, corn, cottonseed, soybean and peanut but not olive oil. The are also present insmall amounts in meat, milk, eggs, leafy plant and some fruits. Fish liver oils, so abundant invitamin A and D, are devoid of vitamin E. Of all the tocopherols discovered so far, the α-formhas the widest distribution and greatest biologic activity. The relative biologic potencies of varioustocopherols are :

α-tocopherol—100β-tocopherol—25

γ-tocopherol—19

The vitamin E content of some oils are presented in Table 33–4.

Table 33–4. Vitamin E content of some oils

Oil Vitamin E

(mg/100 g)

Groundnut 261Wheatgerm 225

Soybean 166

Linseed 110Palm 56

Mustard 32

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C. Structure. Vitamin E is the collective name for a group of closely related lipids calledtocopherols. The tocopherols are derivatives of 6-hydroxychroman (also known as tocol)bearing an isoprenoid side chain at carbon 2. The structure of a-tocopherol (C29H50O2) is givenin Fig. 33–9.

Fig. 33–9. ααααα-tocopherol(5,7,8-trimethyl tocol)

The various tocopherols differ from each other in substituents on carbons 5, 7 and 8. Thesesubstituents are methyl groups and hydrogen atoms. a-tocopherol contains 3 methyl groups whereasother tocopherols are short one or two methyl groups on the aromatic ring (refer Table 33–3).

Table 33–3. Composition of the variable segment of different tocopherols

Types of Tocopherol Substituents at Carbon Atoms

5 7 8

Alfa α CH3 CH3 CH3

Beta β CH3 H CH3

Gamma γ H CH3 CH3

Delta δ H H CH3

Epsilon ∈ CH3 H H

Zeta ζ CH3 CH3 H

Eta η H CH3 H

It is noteworthy that the presence of all 3 methyl groups attached to the benzene ring isnecessary for full activity. d-tocopherol has but one methyl group and is almost without activity.A slight change in the structure of the tocopherols, for example shortening the side chain, maygreatly diminish their physiologic activity.

D. Properties. Vitamin E is a light yellow oil. It is resistant to heat (up to 200°C) and acidsbut acted upon by alkalies. It is easily but slowly oxidized and is destroyed by UV rays. Thetocopherols are excellent antioxidants. They prevent other vitamins presents in food (e.g., vitaminA) from oxidative destruction. It is found in the nonsaponifiable fraction of the vegetable oils.

E. Metabolism. Tocopherols act as antioxidants, i.e., they can prevent the oxidation ofvarious other easily oxidized substances such as fats and vitamin A. It is for this reason that theyare commercially added to foods to retard their spoilage. It may be recalled that vitamin A isessential for reproduction. Whereas the beneficial action of vitamin A is mainly on the ectodermand endoderm, that of vitamin E is on the mesodermal tissue. But, very likely, vitamin E influencesall the 3 germinal layers of the embryo by preventing the too rapid destruction of vitamin A.Certain substances such as phenols and vitamin C (ascorbic acid) stimulate the antioxidant propertyof vitamin E.

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In fact, the biochemical activity of tocopherol lies in its capacity to protect mitochondrialsystem from inactivation by fat peroxides. Thus, in mitochondria obtained from vitamin E-deficientanimals, a marked deterioration in activity is found due to peroxidation of unsaturated fatty acidswhich are usually present in these particles. Addition of vitamin E prevents this deterioration byacting as antioxidant for peroxidation.

It has been observed that tocopherol-deficient muscles (esp., cardiac and skeletal) show ahigh oxygen uptake. Administration of tocopherol brings down the oxygen consumption to normal.

The catabolism of α-tocopherol involves both the oxidative cleavage of the chroman ring toyield quinone or hydroquinone-like compounds and the degradation of the isoprenoids side chain(Simon, 1956)

F. Deficiency. The characteristic symptoms of experimentally-induced vitamin E deficiencyvary from animal to animal. In mature female rats, sterility develops because of reabsorption offetus after conception while in males, the germinal epithelium of the testes degenerates and thespermatozoa become nonmotile.

Avitaminosis E in herbivorous animals like rabbits and guinea pigs leads to acute musculardystrophy (atrophy of muscle fibres), which ultimately results in creatinuria ; young chicks exhibitcapillary damage and encephalomalacia ; hen eggs show low hatchability and monkeys revealhemolytic anemia. There is, however, little evidence that man is ever short of vitamin E.

Finally, as is true for almost all the vitamins, avitaminosis E prevents normal growth. It alsosometimes causes degenatation of the renal tubular cells.

G. Human requirements. Vitamin E is not a problem in human nutrition because it isubiquitous in foods. However, the minimum daily requirement of vitamin E for adults is 30 I.U.for men and 25 I.U. for women. The pregnant and lactating mothers, however, require 30 I.U.daily. For infants and children,. the vitamin E requirement is at the rate of 1 to 1.25 I.U. perkilogram of body weight. One International Unit of dl-α-tocopherol is equivalent to the biologicactivity of 1.1 mg of pure compound or 0.67 mg of d-α-tocopherol.

VITAMIN KA. History. Henrick Dam (1929), a Danish

investigator, found that newly-hatched chicks, fed onartificial diets, develop hemorrhage, a fatal diseasecharacterized by prolonged blood-clotting period. Theterm vitamin K (K for Danish koagulations) was thenproposed by Dam (1934) himself to designate the activefactor which cured or prevented this disease. On accountof its blood-clotting power, it is also called asantihemorrhagic factor or coagulation vitamin.

Henrick Dam (LT, 1895-1976) wason a lecture tour of the United Statesand Canada when the Nazisoccupied his homeland, Denmark,in 1940. He spent the war years atthe University of Rochester, and itwas during this period that hereceived his Nobel Prize (1943).

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Fig. 33–10. Two vitamins of K group

Of the 2 naturally-occurring forms of this vitamin, vitamin K1 was first isolated by Dam etal from alfalfa in 1939 and the other form, vitamin K2 from fish meal by Doisy et al, also in 1939.

B. Occurrence. Vitamin K1 occurs in green vegetables like spinach, alfalfa, cabbage etc.Fruits and cereals are poor sources. Vitamin K2 is found in some intestinal bacteria. A rich sourceof K2 is putrefied fish meal. Their relative biologic potencies are :

vitamin K1—100vitamin K2—80

C. Structure. Chemically, the two forms of vitamin K (Fig. 33–10) are derivatives ofquinones and differ from each other in the composition of their side chain present at carbon 3 ofthe naphthoquinone ring. It is a phytol radical in vitamin K1 (C31H46O2) and a difarnesyl radicalin vitamin K2 (C41H56O2). Vitamin K1, found in plants, has 4 isoprene units in its side chainwhereas vitamin K2, found in animals, contains in its side 6 isoprene units, each with a doublebond.

Analogues— The various analogues of naphthoquinone, however, have also been shown topossess vitamin K activity for animals. This is due to their structural resemblance. The commonexamples are menadione and phthiocol (Fig. 33–11).

Fig. 33–11. Two analogues of vitamin K

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Menadione, which is sometimes referred to as vitamin K3, is twice as potent as vitamin K1.It is soluble in oil, sparingly so in water and is not oxidized in air when protected from light. Itsdiphosphate ester is water-soluble and is widely used clinically.

D. Properties. Vitamin K1 is a yellow viscid oil but vitamin K2 is a yellowish crystallinesolid. It is sensitive to light and is, therefore, kept in dark bottles. It is destroyed by irradiation,strong acids, alkalies and oxidizing agents.

E. Metabolism. Vitamin K plays an essential role in the biosynthesis of prothrombin— ablood plasma protein needed in the process of blood clotting and produced in liver. The processof blood coagulation may be summarized as below.

Fig. 32–12. Probable mechanism of blood coagulation

[Note the role of vitamin K in the synthesis of prothrombin which is a precursor of thrombin, the latter hasdual function of (a) hydrolysing fibrinogen to fibrin and (b) activating fibrinase of FSF, which brings aboutclotting.]

The formation of the blood clot (refer Fig. 33–12) is caused by the enzymic hydrolysis ofthe soluble plasma protein, fibrinogen to the insoluble protein, fibrin and fibrinopeptides. Thistransformation is catalyzed by an enzyme, thrombin. Thrombin itself is not present in the bloodbut is produced from its precursor, prothrombin in the presence of Ca2+ ions and another proteincalled thromboplastin ( = thrombokinase). In the next step, fibrin forms soft, fibrous networks (orsoft clots). Then in the presence of Ca2+, thrombin activates fibrinase, an enzyme precursor foundin blood plasma. Fibrinase is also known as fibrin-stabilizing factor (FSF). Finally, fibrous networksof fibrin link with each other under the influence of activated FSF to produce cross-linked fibrin(or hard clots).

The vitamins K are fat-soluble and are absorbed only in the presence of bile. As a result, theabsorption occurs in the upper portion of the small intestine where bile salts are present. Theavitaminosis K may occur where bile is prevented from entering the intestinal tract. This is truefor most of the fat-soluble vitamins but is, in particular, important in the case of vitamin Kbecause of its blood clotting action.

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Like vitamin E and coenzyme Q, the vitamin K has also been ascribed a role in electrontransport system (ETS) and oxidative phosphorylation in mitochondria. The vitamin K1 and K2both activate electron transport in the succinate oxidase of cardiac muscle preparations that havebeen made inactive by treating with isooctane. The bacterial extracts or liver mitochondria, whenAntagonists irradiated, require vitamin K for oxidative phosphorylation. This suggests a possiblerole of vitamin K in oxidative phosphorylation. The specific site of action is believed to occurbetween NADH and cytochrome b. It has been suggested that a phosphate ester of vitamin K, uponoxidation, transfers phosphate to ADP to form ATP.

Antagonists— Two antagonists of vitamin K are dicumarol and warfarin (Fig. 33–13) ; bothantagonists prevent blood clotting. Dicumarol was first isolated frommouldy clover hay. It is often given to patients, who have sufferedheart attacks caused by blood clots, as as preventive measure againstfurther clotting in the blood vessels. Warfarin (name derived from the initials of the WisconsinAlumni Research Foundation, which sponsored the research on the compound) is a syntheticanalogue of vitamin K. It is extremely poisonous to rats, causing death by internal bleeding.Ironically, this potent rodenticide is also a valuable anticoagulant drug for the treatment of humanpatients in whom excessive bleeding is dangerous— surgical patients and victims of coronarythrombosis.

Fig. 33–13. Two vitamin K antagonists

Note that both dicumarol and warfarin lack an isoprenoid side chain.

In 1988, by introducing the antioxidant vitamin E, David Gershon and his colleagues at theTechnion–Israel Institute of Technology, have succeeded in reducing cell damage and increasingthe life span of nematode worms. The damage body cells sustain is due to oxidation, an underlyingmechanism of ageing, which also damages the disposal system. Paradoxically, the oxygen wedepend on for life is a source of our age-associated decline in function. Similar researches conductedon humans might shed light on how to intervene and retard ageing in them.

F. Deficiency. Deficiency of vitamin K causes loss of blood-clotting power. The infantsmay also show signs of vitamin K deficiency by developing hemorrhage. This disease persistsby the time the bacteria develop in the intestine. Administration of this vitamin to pregnantmothers before parturition decreases the onset of this disease. In man, however, avitaminosis Kresults in steatorrhea with diminished intestinal absorption of lipids.

In general, vitamin K deficiency is rarely found in higher animals as this is provided by foodand also synthesized by intestinal bacteria.

G. Human requirements. There is seldom a lack of sufficient vitamin K in human beings.As such, no standard requirement has been set.

COENZYME QCrane et al (1959) have demonstrated that coenzyme Q and certain other ubiquinones are

components of mitochondrial lipids. These substances serve as electron transport agents and are

Dicumarol is also spelt asdicoumarol.

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involved in the formation of ATP at a cytochrome a. Roles (1967) has classified the coenzymeQ group as vitamins because of their ability to cure (or protect against) vitamin E deficiency inseveral animal species. Some of the coenzymes also participate in electron transport and/or oxidativephosphorylation.

Fig. 33–14. Coenzyme Q

Various homologues of coenzyme Q, containing 6 to 10 isoprene units, have been isolatedfrom various microbes, chloroplasts of green plants and mitochondria of animals. These have thesame quinonoid nucleus (Fig. 32–14) but differ in the number of isoprenoid units in the side chain.For example, coenzyme Q from animal source has 10 isoprene units and is, henceforth, calledcoenzyme Q10 or ubiquinone50 (50 carbon atoms, i.e., 10 isoprene units, in the side chain), whereasthe one from bacteria has less than 10 isoprene units. Mycobacteria, however, contain nocoenzyme Q.

STIGMASTEROLAnother alleged fat-soluble vitamin is stigmasterol. It is a plant sterol and has been isolated

from soybean and wheat germ oils. It in present in alfalfa and fresh cream. Chemically, itresembles ergosterol closely and contains only 2 double bonds at carbon postitons 5—6 and22—23 (Fig. 33–15). The absence of stigmasterol causes stiffness of the wrists and elbows ofthe guinea pigs. For this reason, it is commonly called as ‘antistiffness factor’. The musclesatrophy and become streaked.

Fig. 33–15. Stigmasterol

Contents


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Contents


REFERENCES

1. Baker H : Clinical Vitaminology. Interscience Publishers, Inc., New York. 1968.

2. Briggs MH (editor) : Vitamins in Human Biology and Medicine. CRC Press, BocaRaton, Fla. 1981.

3. Briggs MH (editor) : Recent Vitamin Research. CRC Press, Boca Raton, Fla, 1984.

4. British Medical Journal : The Nutrition of Man. Vol. 37, 1981.

5. Davidson S, Passmore R, Brock JF, Truswell AS (editors) : Human Nutrition andDietetics. 6th ed. Churchill Livingstone Ltd., Edinburgh. 1975.

6. DeLuca HF : The Vitamin D Story. FASEB J. 2 : 224-236, 1988.

7. Dyke SF : The Chemistry of the Vitamins. Interscience Publishers, Inc., New York. 1965.

8. Ganguly J : The “British Eyes” Vitamin. Science Today. 30-33, 1973.

9. Goodwin TW : The Biosynthesis of Vitamins and Related Compounds. Academic Press,Inc., New York. 1963.

10. György P, Pearson WN (editors) : The Vitamins. Vols. 6 and 7. Academic Press, Inc.,New York. 1967.

11. Harris LJ : Vitamins in Theory and Practice. Cambridge University. Press, Cambridge.1965.

12. Harris LJ : The Discovery of Vitamins : in J. Needham’s (ed) : The Chemistry of Life.150-170. Cambridge University. Press, New York. 1970.

13. Hauschka PV, Lian BJ, Gallop PM : Vitamin K and mineralization. Trends Biochem.Sci. 3 : 75, 1978.

14. Holman WIM : Distribution of vitamins within the tissues of common foodstuffs. Nutr.Abstr. Revs., 26 : 227-304, 1956.

15. Isler O, Wiss O : Chemistry and biochemistry of the K vitamins. Vitamins and Hormones.17 : 54-91, 1959.

16. Keys A : The caloric requirement of adult man . Nutr. Abstr. & Revs., 19 : 1-21, 1949.

17. Kleiber M : The Fire of Life. Wiley, New York. 1961.

18. Loomis WF : Rickets. Sci. Amer. 223 : 76-91, 1970.

19. Machlin LJ (editor) : Vitamin E. A Comprehensive Treatise. M.Dekker. 1980.

20. Marks J : The Vitamins in Health and Disease. Little Brown & Co., Boston. 1969.

21. McCormick DB, Wright LD : Vitamins and coenzymes. In the series Methods inEnzymology., Vols. 62, 66 and 67. Academic Press, Inc., New York. 1979, 1980.

22. Meites J, Nelson MM : Effects of hormonal imbalances on nutritional requirements.Vitamins and Hormones, 20 : 205-236, 1960.

23. Miller SJH : Parsons’ Diseases of the Eye. 16th ed., ELBS. 1978.

24. Moore T : Vitamin A. Elsevier Publishing Co., Amsterdam. 1957.

25. National Research Council : Recommended Dietary Allowances. National Academy ofSciences (U.S. ), 1980.

26. Nicolaysen R, Eeg-Larsen N : Biochemistry and physiology of vitamin D. Vitamins andHormones 11 : 29-61, 1953.

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27. Pett LB : Vitamin requirements of human beings. Vitamins and Hormones. 13 : 214-238,1955.

28. Readings From Scientific American : Human Nutrition. Freeman, San Francisco. 1978.

29. Roels OA : Present knowledge of vitamin A. Nutr. Rev. 24 : 129, 1966.

30. Sebrell WH (editor) : Control of Malnutrition in Man. Amer. Public Health Asso., NewYork. 1960.

31. Sebrell WH Jr, Harris RS (editors) : The Vitamins : Chemistry, Physiology, Pathologyand Methods. 2nd ed. Vols. 1-5. Academic Press, Inc., New York. 1967-1972.

32. Sobel AE : The absorption and transportation of fat-soluble vitamins. Vitamins andHormones 10 : 47-68, 1952.

33. Vasington FD, Reichard SM, Nason A : Biochemistry of vitamin E. Vitamins andHormones. 20 : 43-88, 1960.

34. Wagner AF, Folkers K : Vitamins and Coenzymes. Interscience Publishers. Inc., NewYork. 1964.

35. Wasserman RH, Corradino RA : Metabolic roles of vitamin A and D. Ann. Rev. Biochem.,40 : 501, 1971.

36. Wasserman RH, Taylor AN : Metabolic roles of vitamin D, E, and K. Ann. Rev. Biochem.,41 : 179, 1972.

37. Wohl MG, Goodhart RS (editors) : Modern Nutrition in Health and Disease. Lea andFebiger, Philadelphia. 1968.

PROBLEMS

1. In contrast to water-soluble vitamins, which must be a part of our daily diet, fat-solublevitamins can be stored in the body in amounts sufficient for many months. Suggest anexplanation for this difference based on solubilities.

2. In the presence of warfarin, an analogue of vitamin K, several proteins of the bloodcoagulation pathway are ineffective because they cannot bind Ca2+ efficiently. Why ?

3. What is the chemical reaction in which vitamin K participates ? How is this reactioninvolved in blood coagulation and bone formation ?

4. If one takes vitamin E to protect his heart, how much should he take ?

5. Will taking vitamins give one extra energy ?

6. When taking vitamin E, is it okay to take other medicine ?

7. Should one take multivitamin pills containing vitamin D every day as one gets older ?

8. How much exposure to sunlight a person needs to supply his body with enough vitaminD ?

9. Vegetables oils are fortified with :

(a) vitamin A

(b) vitamin D

(c) vitamin E

(d) vitamin K

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10. What needs to be stored in dark bottles ?

(a) biotin

(b) nicotinic acid

(c) riboflavin

(d) retinol11. One claim put forth by purveyors of health foods is that vitamins obtained from natural

sources are more healthful than those obtained by chemical synthesis. For example, it isclaimed that pure L-ascorbic acid (vitamin C) obtained from rose hips is better for youthan pure L-ascorbic acid manufactured in a chemical plant. Are the vitamins from thetwo sources different ? Can the body distinguish a vitamin’s source ?

12. How much vitamin D a person needs daily to help prevent osteoporosis ?

13. Is it safe to take very high doses of vitamin D ?

14. Vitamin A is the essential dietary factor for the formation of :

(a) rhodopsin

(b) biliverdin

(c) hemoglobin

(d) biotin

15. Which of the following is both a vitamin and a hormone ?

(a) ascorbic acid

(b) calciferol

(c) thiamine

(d) riboflavin

16. Does your skin ever lose its ability to make vitamin D from sunlight ?

17. When is a good time to take your multivitamin/mineral tablet ?18. If a person takes a daily multivitamin and supplements, can he get away with less fruits,

vegetables and grains ?19. Can one take vitamins with thyroid pills ?20. The most nutritive substance on Earth is :

(a) Spinach(b) Spirulina

(c) Laminaria

(d) Soybean

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